Type 2 diabetes (T2D) is a multi-organ damaging, debilitating and lethal disease on an epidemic scale. According to Center for Disease Control and Prevention, at least 54 million American adults had pre-diabetes and 23.6 million had diabetes. The obesity rates in the US have now reached 32.2% and 35.5% among adult men and women. Even more concerning, children with T2D are on the rise along with their rising obesity rates. Thus, T2D poses a grave threat to human health and an escalating burden to the health care system. Current therapies are far from ideal. They manage blood glucose but poorly address the causes and fail to stop the disease. We wish to use muscle as a platform for T2D gene therapy, since muscle is the largest organ in the body and a major site for insulin-mediated glucose homeostasis and energy consumption. Based on our encouraging preliminary studies, we will continue to use adeno-associated virus as the muscle gene delivery vector, myostatin propeptide and follistatin as the therapeutic genes, the commonly used leptin receptor defective T2D/obesity mice (db/db) as the animal model, to test our hypothesis that skeletal muscles can be an effective platform for T2D gene therapy. We will systematically evaluate and improve the therapeutic efficacies as well as safety profiles. We will also investigate potential molecular mechanisms that substantiate the clinical outcomes. The success of this proposal should lead to a new, effective and safe therapy for T2D.